Codex_V5

Geno- and phenotypic characterization of human cytomegalovirus mutants selected in vitro after letermovir (AIC246) exposure.

Abstract: Letermovir is a novel antiviral compound currently in clinical development for the prevention of human cytomegalovirus (HCMV) infections. In contrast to all currently approved anti-HCMV drugs that target the viral DNA polymerase, letermovir acts via a distinct mode of action involving the viral terminase subunit pUL56. To extend our understanding of potential letermovir resistance mechanisms, we used marker transfer to characterize mutations identified in letermovir-resistant HCMV variants that were selected in cell culture.

Mutant	Gene	Virus	Antiviral	EC50 ratio	Phenotype
V231L	UL56	Human betaherpesvirus 5	Letermovir	5.00	High level resistance
V236M	UL56	Human betaherpesvirus 5	Letermovir	45.00	High level resistance
L241P	UL56	Human betaherpesvirus 5	Letermovir	218.00	High level resistance
C325Y	UL56	Human betaherpesvirus 5	Letermovir	8796.00	High level resistance
R369G	UL56	Human betaherpesvirus 5	Letermovir	44.00	High level resistance
R369M	UL56	Human betaherpesvirus 5	Letermovir	13.00	High level resistance
R369S	UL56	Human betaherpesvirus 5	Letermovir	48.00	High level resistance
R396S	UL56	Human betaherpesvirus 5	Letermovir	81.00	High level resistance